Abstract/Project Summary Dogma tells us that oxygen (O2) is an absolute requirement for cell/tissue survival. We have recently discovered a unique skeletal muscle that is remarkably and uniquely resistant to negative effects of ischemia. The implication is that unlike other peripheral skeletal muscles, this muscle has a distinct mechanism that allows it to tolerate ischemic conditions. Identifying the underlying mechanism(s) that explain the ischemia resistance could hold the key to unlocking therapeutic targets and/or approaches for improving tissue survival under conditions where O2 exposure is limiting. Ischemia affects skeletal muscle in numerous clinical conditions, including various myopathies, peripheral artery disease (PAD), compartment syndrome, severe limb injury, etc., not to mention coronary occlusion in cardiac muscle. Thus, the identification of a mechanism that provides ischemia resistance would overcome one of the longest standing challenges faced by clinicians. Using an integrative experimental design, the scientific goal of this project is to elucidate the unique functional, metabolic, and/or bioenergetic systems that account for the ability of this muscle to survive ischemic insults. The long-term goal of the project is to leverage the identified mechanism(s) to therapeutically treat and/or prevent myopathies induced or exacerbated by ischemia. The proposal will use molecular, biochemical, and physiological approaches designed to address hypotheses grounded in the idea that this unique muscle must be able to meet energetic demands and ensure sarcolemmal stability during ischemia. Thus, the experimental approach seeks to leverage already identified genes that are critical to the generation of adenosine triphosphate and manipulate genes that are able to stabilize the sarcolemma during ischemic conditions to prevent excitotoxicity. Using gain-of or loss-of function approaches the experiments designed in the proposal will determine if the mechanism is necessary for ischemia survival and also assess if the mechanism is sufficient to survive ischemia. Completion of this proposal will challenge dogma concerning our understanding of how tissue can resist ischemic insults and advance the field forward in a significant fashion due to the identification of an ischemia-resistant muscle.